Abstract
Overexpression of pro-inflammatory cytokines and cellular energy failure are associated with neuroinflammatory disorders, such as Alzheimer's disease. Transgenic mice homozygous for human ApoE4 gene, a well known AD and atherosclerosis animal model, show decreased levels of ATP, increased inflammatory cytokines level and accumulation of beta amyloid in the brain. All these findings are considered responsible for triggering cognitive decline. We have demonstrated that a single administration of the bacterial E. coli protein toxin CNF1 to aged apoE4 mice, beside inducing a strong amelioration of both spatial and emotional memory deficits, favored the cell energy restore through an increment of ATP content. This was accompanied by a modulation of cerebral Rho and Rac1 activity. Furthermore, CNF1 decreased the levels of beta amyloid accumulation and interleukin-1β expression in the hippocampus. Altogether, these data suggest that the pharmacological modulation of Rho GTPases by CNF1 can improve memory performances in an animal model of Alzheimer's disease via a control of neuroinflammation and a rescue of systemic energy homeostasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Alzheimer Disease / physiopathology
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Amyloid beta-Peptides / metabolism
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Animals
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Apolipoprotein E4 / genetics
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Bacterial Toxins / pharmacology*
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Bacterial Toxins / therapeutic use
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Biomarkers / metabolism
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Brain / drug effects*
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Brain / metabolism*
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Brain / physiopathology
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Cognition / drug effects*
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Cytokines / metabolism
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Disease Models, Animal
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Energy Metabolism / drug effects*
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Enzyme Activation / drug effects
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Escherichia coli Proteins / pharmacology*
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Escherichia coli Proteins / therapeutic use
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Hippocampus / drug effects
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Hippocampus / metabolism
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Hippocampus / pathology
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Hippocampus / physiopathology
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Humans
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Inflammation / metabolism
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Memory / drug effects
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Mice
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Mice, Transgenic
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Signal Transduction / drug effects
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Spatial Behavior / drug effects
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Spatial Behavior / physiology
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rho GTP-Binding Proteins / metabolism
Substances
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Amyloid beta-Peptides
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Apolipoprotein E4
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Bacterial Toxins
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Biomarkers
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Cytokines
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Escherichia coli Proteins
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cytotoxic necrotizing factor type 1
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Adenosine Triphosphate
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rho GTP-Binding Proteins
Grants and funding
This work was partially supported by “Italia-USA Collaboration Program”, Fascicolo 11US/1 (to CF) and by the Cure_FXS project (
www.cure-fxs.eu) under the E-Rare program (to CF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.